title: Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter.
abstract: To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhanbin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Prashanth K
authors.initials: PK
authors.lastname: Padakanti
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cui
authors.forename: Aixiao
authors.initials: A
authors.lastname: Li
authors.forename: Dexing
authors.initials: D
authors.lastname: Zeng
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Hubert
authors.initials: H
authors.lastname: Flores
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D018360:Crystallography, X-Ray; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: C584252:(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-(methylamino)phenyl)methanone; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D008024:Ligands; D009284:Naphthols; D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D050494:Vesicular Acetylcholine Transport Proteins